PROCESS FOR THE PREPARATION OF UNSATURATEP ESTERS
This invention relates to processes for the preparation of certain unsaturated esters.
Statins represent the most important class of hypolipidemic and hypocholesterolemic agents. For example, Atorvastatin ((2R-trans)-5-(4-fluorophenyl)-2- (1-methylethyl)-N,4-diphenyl]-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H- pyrrole-3-carboxamide (U.S. Pat. Nos. 4,647,576 and 4,681 ,893)) is the active agent in Lipitor™, one of the most widely used pharmaceuticals in the world.
A number of different approaches to the synthesis of statins have been reported in the literature (see for example JP 08127585; EP 705837; J. Med. Chem., (1990), 33, (11 ), 2982; Tet. Lett., (1990), 31 , (18), 2545; CN 1102644; US 4650890).
In particular, WO 01/96347 discloses the reaction between tert-butyl 6-oxo-3,5- isopropylidene-dioxyhexanoate (BHA aldehyde) and activated phosphorous compounds. However this reaction is significantly disadvantaged since BHA aldehyde is unstable and so the reaction must be carried out at extremely low temperatures i.e. -78°C. According to the present invention there is provided a process for the preparation of a compound of Formula (1 );
Formula (1) wherein:
R1 and R2 are each independently hydroxy protecting groups; R3 is optionally substituted Chalky!; R4 is an organic group; and R5 is H, an organic group or R4 and R5 together with the C atom to which they are attached form a ring which is a component of an organic group: which comprises reacting a compound of Formula (2);
Formula (2)
wherein R1, R2 and R3are as defined above;
with an oxidising agent in the presence of a compound of formula R4-CHR5-Y wherein R4 and R5 are as defined above and Y represents a group forming a Wittig reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner-Wadsworth Emmons reagent; a Warren reagent; or a ylid precursor; and optionally a base.
The hydroxy protecting groups, R and R2, include such protecting groups as are commonly employed to protect hydroxy groups, for example those protecting groups disclosed in Protecting Groups in Organic Synthesis Green & Wuts; Wiley, incorporated herein, in its entirety, by reference. Examples of protecting groups, which may be utilised, include benzyl groups, tetrahydropyranyl groups and trialkylsilyl groups, such as tri-C^-alkylsilyl, especially t- butyldimethylsilyl groups.
In a preferred embodiment R1 and R2 together with the oxygen atoms to which they are attached comprise an optionally substituted ring system. It is particularly preferred that R1 and R2 form a 1 ,3 dioxane ring via the oxygen atoms to which they are attached.
Optional substituents on R3 are preferably selected from: optionally substituted alkoxy (preferably C^-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphato, sulpho, nitro, cyano, halo, ureido, -SO2F, hydroxy, ester, -NRaR , -CORa, -CONRaR , -NHCORa, carboxyester, sulphone, and -SO2NRaR wherein Ra and Rb are each independently H, optionally substituted alkyl (especially C^-alkyl) or optionally substituted aryl (preferably phenyl), or, in the case of -CONRaRb and -SO2NRaR , Ra and Rb together with the nitrogen atom to which they are attached may represent an aliphatic or aromatic ring system. Optional substituents for any of the substituents described for R3 may be selected from the same list of substituents and optionally substituted alkyl (preferably C^-alkyl).
Optional substituents on R1 and R2 are preferably each independently selected from those substituents preferred for R3 and optionally substituted alkyl (preferably C^- alkyl). Optional substituents for any of the substituents described for R1 and R2 may be selected from the same list of substituents.
Organic groups represented by R4 may comprise optionally substituted linear branched or cyclic alkyl, alkenyl or alkynyl, optionally substituted aryl, optionally substituted heterocyclyl or any combination thereof.
Preferably R4 comprises one, two or more optionally substituted rings, preferably 5 or 6 membered-rings, often comprising at least one cyclic or heterocyclic aromatic group, commonly comprising a 5 or 6 membered aromatic ring, which may be substituted by one or more of the substituents described above for R\ R2 and R3. Preferred substituents include one or more cyclic groups, which may form a conjugated bicyclic ring system, one or more aryl substituents, especially phenyl substituents, which may themselves be
substituted, and one or more alkyl substituents, including cycloalkyl substituents. Electron withdrawing substituents such as: CORa; -COORa; nitro; cyano; halo, especially F, Cl and Br; sulfo; CZ3> wherein Z is F or Cl; -SO2F; -CONRaRb; and -SO2NRaRb; wherein Ra and Rb are as defined above: are particularly preferred.
Commonly, R4 comprises a heteroaromatic group, often comprising one or two heteroatoms, most commonly nitrogen atoms.
Preferably R4 comprises one or more of the following ring systems which may be substituted, at any position, preferably with an electron withdrawing substituent:
Organic groups represented by R5 may comprise optionally substituted linear branched or cyclic alkyl (especially linear or branched C^-alkyl), optionally substituted aryl (preferably phenyl), optionally substituted heterocyclyl or any combination thereof. Optional substituents for R5 are as described for R1, R2 and R3 above. Preferably R5 is H.
In the preferred compounds of R4-CH2-Y, the functional group -CH2-Y may be attached at any available position of the ring or may be attached to a ring substituent.
Compounds of formula R4-CHR5-Y may be prepared by reacting a compound of formula R4-CHR5-X, where X represents OH, O(COR6) or a leaving group, and R6 represents a hydrocarbyl group, preferably a C^ alkyl group, with a reagent suitable for the formation of a Wittig reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner-Wadsworth Emmons reagent; a Warren reagent; or a ylid precursor.
Examples of leaving groups that can be represented by X include halogen, especially Cl, Br and I, optionally substituted aryl or alkyl sulphonates especially tosylate, brosylate, mesylate, trifluoromesylate and t flate.
The reaction takes place under conditions known in the art for the formation of the given Wittig, Horner-Wadsworth Emmons or Warren reagent depending on the nature of group Y, such conditions are summarised in Chem. Rev. 1989, 863-927 which is incorporated herein, in its entirety, by reference.
Commonly, the reaction takes place in the presence of an inert organic solvent.
Both polar and non-polar solvents may be employed, particularly aprotic solvents, and examples include: hydrocarbons, especially toluene; chlorocarbons, especially dichloromethane and chloroform; nitriles, such as acetonitrile; ethers, including dioxane and tetrahydrofuran; and amides such as dimethylformamide.
In one preferred embodiment of the present invention Y represents a group forming a Wittig reagent, that is of formula P(R7)3 (or the corresponding As or Sb compounds), where R7 is preferably C^ alkyl or aryl, and most preferably P(phenyl)3.
In another preferred embodiment of the present invention Y represents a group forming a Horner-Wadsworth Emmons reagent, that is of formula (R8O)2P(=O) wherein R8 is alkyl or aryl, preferably C^ alkyl.
In a third preferred embodiment of the present invention Y represents a group forming a Warren reagent, that is of formula (R9)2P(=O) wherein R9 is alkyl or aryl, preferably phenyl. The oxidising agent may be any agent able to oxidise the primary alcohol group in a compound of Formula (2) to the corresponding aldehyde without preventing the further reaction of the aldehyde with the particular compound of formula R4-CHR5-Y.
Thus, the oxidising agent may be any suitable chemical agent or a biological agent.
Preferably the oxidising agent is a chemical agent. Chemical agents able to oxidise a primary alcohol group to an aldehyde are summarised in R.C. Larock Comprehensive Organic Transformations, VCH Publishers, 1989, pages 604, 605 and 607 to 613 which pages are incorporated herein by reference.
Preferred chemical oxidising agents are selected from the following: RuO4; phase transfer oxidant, especially Pr4NRuO4; 2,2,6,6-tetramethyl-1-piperidinyloxy/bleach comprising hypochlorite or hypobromite; Fetizon's reagent (Ag2CO3 on celite); and MnO2.
In a particularly preferred embodiment the oxidising agent is MnO2.
The alkene double bond formed in the compound of Formula (1) may be cis or trans but is preferably predominantly trans.
The process of the present invention is preferably performed in the presence of any organic solvent or mixture of organic solvents which is unreactive towards the reagents employed. Both polar and non-polar solvents may be employed, and example of suitable solvents include hydrocarbons, especially toluene, chlorocarbons, especially dichloromethane and chloroform, nitriles, such as acetonitrile, ethers, including dioxane and tetrahydrofuran, amides such as dimethylformamamide, and ketones, such as acetone.
Preferably, substantially anhydrous conditions are employed.
Depending on the nature of R4-CHR5-Y and the reaction conditions a base may be required.
Preferred bases include alkyl lithium; alkali metal hydride; alkoxide salts, such as an alkali metal alkoxide; alkali metal amine, for example sodamide or lithium diisoproplyamide; an alkali metal 1 ,1 ,1 ,3,3,3-hexamethyldisilazane salt or an alkali metal hydroxide.
In one preferred embodiment a compound of Formula (2) is reacted with an oxidising agent in the presence of the compound of R4-CHR5-Y and a base, wherein R4 and R5 are as defined above.
The process of the present invention is preferably performed at a temperature greater than 0°C and more preferably at a temperature greater than 50°C and especially at a temperature greater than 100°C.
It is particularly preferred that the reaction is carried out at a temperature in the range of from 50°C to 250°C, especially in the range of from 80°C to 140°C.
In one embodiment the process of the present invention is performed under reflux. The process is advantageously allowed to proceed to at least 90% conversion to a compound of Formula (1).
The reaction time of the process of the present invention will depend on a number of factors, for example the reagent concentrations, the relative amounts of reagents and particularly the reaction temperature. Typical reaction times, in addition to the reagent addition times, range from 1 minute to 300 hours, with reaction times of 5 minutes to 100 hours being common.
In view of the above preferences a favoured process is for the preparation of a compound of Formula (3);
Formula (3) wherein:
R4 is an organic group which comprises one, two or more rings; and
R5 is H, an organic group or R4 and R5 together with the C atom to which they are attached form a ring which is a component of an organic group: which comprises reacting a compound of Formula (4);
H3C CH,
. CH
»°x^xx0x CH,
Formula (4)
with an oxidising agent in the presence of a compound of formula R4-CHR5-Y wherein R4 and R5 are as defined above in Formula (3) and Y represents a group forming a Wittig
reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner-Wadsworth Emmons reagent; a Warren reagent; or a ylid: and optionally a base.
A more preferred embodiment of the present process is a process for the preparation of a compound of Formula (5);
Formula (5) wherein:
R4 is an organic group comprising one or more of the following ring systems:
which comprises reacting a compound of Formula (6);
Formula (6)
with MnO2 in the presence of a compound of formula R4-CH2-Y where R4 is as defined in Formula (5) and Y represents a group forming a Wittig reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner- Wadsworth Emmons reagent; a Warren reagent; or a ylid: a solvent and optionally a base.
A second aspect of the invention provides a process for the preparation of a compound of Formula (1 );
Formula (1)
wherein:
R1 and R2 are each independently hydroxy protecting groups;
R3 is optionally substituted Chal y!;
R4 is an organic group; and R5 is H, an organic group or R4 and R5 together with the C atom to which they are attached form a ring which is a component of an organic group: which comprises the steps:
(a) reacting a compound of formula R4-CHR5-X, wherein R4 and R5 are as defined above and X represents OH, O(COR6) or a leaving group, where R6 represents H or a hydrocarbyl group, with a reagent suitable for the formation of a Wittig reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner-Wadsworth Emmons reagent; a Warren reagent; or a ylid precursor, to give a compound of formula R4-CHR5-Y where Y represents a group forming a Wittig reagent; a P, As or Sb-containing Horner-Wadsworth Emmons reagent; a P(lll), As (III) or Sb(lll) precursor of a Horner-Wadsworth Emmons reagent; a Warren reagent; or a ylid precursor; and
(b) reacting a compound of Formula (2);
Formula (2)
wherein R\ R2 and R3are as defined above; with an oxidising agent in the presence of the compound of R4-CHR5-Y formed in step (a), and optionally a base.
R1, R2, R3, R4 , R5 and compounds of Formulae (1 ) and (2) are as preferred in the first aspect of the invention.
Oxidising agents, optional bases, compounds of formula R4-CHR5-X, Wittig reagents, Horner-Wadsworth Emmons reagents, precursors thereof, Warren reagents and ylid precursors are also as preferred in the first aspect of the invention.
Reaction conditions for step (a) and step (b) are as described and preferred in the first aspect of the invention.
A third aspect of the invention provides a process for the preparation of a compound of Formula (7);
Formula (7)
which comprises reacting a compound of Formula (2), as defined above, with an oxidising agent selected from the group consisting of MnO2, MnO4; bromine; CrO3 in hexamethylphosphoramide; RuO4; a phase transfer oxidant, especially Pr4NRuO4; 2,2,6,6- tetramethyl-1-piperidinyloxy/bleach comprising hypochlorite or hypobromite; and Fetizon's reagent (Ag2CO3 on celite).
Preferably the oxidising agent is MnO2, RuO4; a phase transfer oxidant, especially Pr4NRuO4; 2,2,6,6-tetramethyl-1-piperidinyloxy/bleach comprising hypochlorite or hypobromite; and Fetizon's reagent (Ag2CO3 on celite) more preferably the oxidising agent is MnO2. R\ R2, R3and compounds of Formula (2) are as preferred in the first aspect of the invention.
Compounds of Formulae (1 ) to (7) that comprise acid or basic groups may exist either as a free acid or base or in the form of a salt. Thus, the Formulae shown herein include compounds in both forms. The compounds of Formulae (1 ) to (7) may exist in tautomeric forms other than those shown in this specification. These tautomers are included within the scope of the present invention.
The invention is further illustrated below wherein all parts and percentages are by weight unless otherwise stated.
Example 1
Process for the preparation of a compound of formula:
Stage 1
Preparation of benzyltriphenylphosphonium bromide
Triphenylphosphine (7.868 g, 1.0 equivalent) and benzyl bromide (3.73 ml, 1.04 equivalent) were dissolved in dimethyl formamide (DMF) (30 ml) and added to a 100 ml round-bottomed flask equipped with a reflux condenser. The reaction mixture was heated to reflux for 1 h and then cooled to room temperature. The precipitated white crystalline solid was collected by filtration, washed with diethyl ether (100 ml) and dried at 60°C under vacuum for 5 h (12.676 g, 98 %).
Stage 2
All glassware was dried in an oven and cooled in a desiccator before use. The reaction was conducted under a nitrogen atmosphere. A three necked 100ml round- bottomed flask was equipped with thermometer, reflux condenser, nitrogen inlet and subaseal™. Benzyltriphenylphosphonium bromide (1.997 g, 1.2 equivalent, prepared as described in Stage 1) was charged to the reaction flask, mixed with tetrahydrofuran (40 ml) and cooled to 0°C. Potassium terf-butoxide (0.517 g, 1.2 equivalent, from Acros) was then added to the vessel causing an immediate orange coloration of the suspension which was stirred at 0°C for 1 h. (ΘS-Hydroxymethyl^^-dimethyl-tl .SJdioxan-^R-ylJ-acetic acid tenSbutyl ester (BHA) (1.119 g, 1.0 equivalent, prepared by a method as described in WO01/85975 A1) was dissolved in toluene (10 ml) and added to the reaction mixture followed by MnO2 (1.168 g, 3.5 equivalent, reagent activated in oven at 110°C for 24 h prior to use). The reaction mixture was maintained at 0°C for 1 h before being allowed to warm to room temperature and stirred for a further 16 h. The reaction mixture was then warmed to 50°C for 18 h and further activated MnO2 (1.168 g, 3.5 equivalent) was added before the reaction mixture was heated to reflux for 69 h. The mixture was then filtered through celite which had been washed with toluene (40 ml). The filtrate was concentrated in vacuo to give 2.172 g of an orange oil which was dissolved in hexane (5 ml) and loaded onto a column of silica gel (40 g) saturated with hexane. The column was washed with a gradient from 100% hexane to 5% ethyl acetate/hexane, analysing fractions by TLC stained with ammonium molybdate to aid visualisation. Fractions containing the component with Rf = 0.50 (eluted at around 50% ethyl acetate/hexane/hexane) were combined and concentrated in vacuo to give 54 mg of a yellow oil. 1H NMR analysis of the material in CDCI3 provided a spectrum of the product in high purity and the coupling constant of the alkene protons (J 11.7 Hz) confirmed the trans nature of the alkene double bond.
Example 2
Process for the preparation of a compound of formula:
All glassware was dried in an oven and cooled in a desiccator before use, the reaction was conducted under a nitrogen atmosphere. A 25 ml round-bottomed flask was equipped with a reflux condenser and nitrogen inlet. BHA (224 mg, 1.0 equivalent; dissolved in toluene 10ml) and (carbethoxymethylene)triphenylphosphorane (408 mg, 1.5 equivalentalents, from Acros) were added to the vessel followed by MnO2 (237 mg, 3.5
equivalent, reagent supplied by Acros - sold as precipitated MnO2 active 88%). The reaction mixture was heated to reflux and additional MnO2 (237 mg, 3.5 equivalent) was added after 0.25 h and again after 0.75 h. The reaction mixture was maintained at reflux for a total of 16 h and then filtered through celite which had been washed with toluene (40 ml). The filtrate was concentrated in vacuo to give 608 mg of a brown oil containing some white crystalline solid. This material was further purified by column chromatography on silica gel (40 g) saturated with hexane, as described in Example 1 , Stage 2. Those fractions which on analysis by TLC contained the component with Rf = 0.79 (TLC eluent = 50% ethyl acetate/hexane) were combined and concentrated in vacuo. The crude product concentrate (608 mg) dissolved in 5% ethyl acetate/hexane (2 ml) was loaded onto a column of silica gel (12 g) saturated with hexane and eluted with 5% ethyl acetate/hexane. Fractions were combined in batches and concentrated in vacuo. 1H NMR analysis of the material in CDCI3 provided a spectrum of the product. The yield was 41 %.